The results of recent clinicopathological studies of human amnesic patients strongly support the long held view that the hippocampal formation plays an essential role in normal memory processing. Individuals with damage limited to the hippocampal formation demonstrate a profound inability to recreate a record of day-to- day events though most post memories remain intact. The hippocampal formation thus appears to play a role in consolidating new memories but is clearly not the long term repository of memory. Research carried out in the post several years of this program has dealt with a wide spectrum of issues including the neurogenesis and morphogenesis of the hippocampal formation, the maturation of its cells in tissue culture, the organization of its intrinsic and extrinsic connections in the developing and mature brain, and morphological plasticity following partial experimental denervation. In the present proposal we will narrow the scope of the work and focus on elucidating the organization of the mature neuronal circuitry which might underlie the role of the hippocampal formation in memory processing. We will continue, and substantially increase, our efforts in studying the connections of the primate hippocampal formation. Using both anterograde and retrograde tracers we will: study the topographic organization of the perforant path projection from the entorhinal cortex to the dentate gyrus and hippocampus; determine the full complement of neocortical interconnections with the subicular complex; precisely define the topographic organization of cortical inputs to the entorhinal cortex and subicular complex; and investigate the cortical and subcortical efferent projections of the entorhinal cortex. The overall objective of these studies is to determine the route by which sensory information enters the hippocampal formation and to uncover the areas to which the hippocampal formation relays its processed information. In the rat, we will carry out studies designed to provide a comprehensive and, where possible, a quantitative summary of the intrinsic circuitry of the hippocampal formation. We will analyze the axonal and dendritic organization of single hippocampal pyramidal cells which have been injected with horseradish peroxidase in the in vitro slice preparation. The processes of these cells will be reconstructed and quantitatively analyzed with a computer-linked three dimensional digitizing system. A second series of experiments will employ the recently developed lectin, anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) to study the topographic organization of the major intrinsic connections of the dentate gyrus and hippocampus. These studies are intended to provide the anatomical information necessary for realistic computational modeling and computer stimulation of hippocampal activity in memory function.